PURPOSE: Renal development regulates prenatal lung growth by maintaining fetal urine output and liquor volume. However, shared signaling pathways underpinning renal and lung morphogenesis indicate that lung hypoplasia in the presence of renal dysgenesis may not result from oligohydramnios alone. We used a transgenic model of renal agenesis/anuria to test whether lung hypoplasia precedes any possible influence of oligohydramnios. MATERIALS AND METHODS: E12 lung primordia from normal and gamma1III4 deficient murine embryos (fetal anuria and renal agenesis-dysgenesis) were cultured for 72 hours. Morphological lung development was measured at 24, 48 and 78 hours by bud counting and tracings of lung epithelial contour using image analysis software and photomicrographs. Genotyping was performed by a separate blinded investigator. RESULTS: E12 homozygous mutant lungs branched but had significant decreases in bud count, epithelial area and perimeter compared to heterozygous or WT controls. These changes presented prior to oligohydramnios and persisted in isolation from the developing renal tract throughout the 72-hour culture period. CONCLUSIONS: Lethal lung hypoplasia seen at term in this model is present from the earliest stages of development, persists in vitro and, therefore, it is not consequent on renal dysfunction. These data implies that 1) fetal interventions for severe prenatal uropathies may have variable success for protecting future lung function and 2) patients with fetal uropathies may warrant greater scrutiny of prenatal lung growth and long-term postnatal lung function.
PURPOSE: Renal development regulates prenatal lung growth by maintaining fetal urine output and liquor volume. However, shared signaling pathways underpinning renal and lung morphogenesis indicate that lung hypoplasia in the presence of renal dysgenesis may not result from oligohydramnios alone. We used a transgenic model of renal agenesis/anuria to test whether lung hypoplasia precedes any possible influence of oligohydramnios. MATERIALS AND METHODS: E12 lung primordia from normal and gamma1III4 deficient murine embryos (fetal anuria and renal agenesis-dysgenesis) were cultured for 72 hours. Morphological lung development was measured at 24, 48 and 78 hours by bud counting and tracings of lung epithelial contour using image analysis software and photomicrographs. Genotyping was performed by a separate blinded investigator. RESULTS: E12 homozygous mutant lungs branched but had significant decreases in bud count, epithelial area and perimeter compared to heterozygous or WT controls. These changes presented prior to oligohydramnios and persisted in isolation from the developing renal tract throughout the 72-hour culture period. CONCLUSIONS: Lethal lung hypoplasia seen at term in this model is present from the earliest stages of development, persists in vitro and, therefore, it is not consequent on renal dysfunction. These data implies that 1) fetal interventions for severe prenatal uropathies may have variable success for protecting future lung function and 2) patients with fetal uropathies may warrant greater scrutiny of prenatal lung growth and long-term postnatal lung function.